General guidance on hold time studies

Manufacturers should ensure that the products that they manufacture are safe,
effective and of the quality required for their intended use. Systems should be
in place to ensure that pharmaceutical products are produced according to
validated processes and to defined procedures. Manufacturing processes should
be shown to be capable of consistently manufacturing pharmaceutical products
that are of the required quality and that comply with their specifications.
Good manufacturing practices (GMP) require that arrangements should
be made to ensure that the dispensed raw materials and packaging materials,
intermediate products, bulk and finished products are stored under appropriate
conditions. Storage arrangements should not have deleterious effects on the
subsequent processing, stability, safety, efficacy or quality of starting materials,
intermediate products and bulk products prior to final packing. Maximum
acceptable holding periods should therefore be established to ensure that
intermediates and bulk product can be held, pending the next processing step,
without producing results outside the acceptance criteria for the quality of the
material. Normally, intermediate and bulk products should not be stored beyond
the established hold time.
The choice of maximum holding period should be supported by relevant
data. Studies may extend beyond the chosen maximum but it is not necessary to
extend testing to determine the extreme limits at which failure occurs.

Glossary
Some important terms used in these guidelines are defined below. They may
have different meanings in other contexts.
Bulk product. Any pharmaceutical product that has completed all
processing stages up to, but not including, final packaging.
Intermediate. Partly processed product that must undergo further
manufacturing steps before it becomes a bulk product.

Scope
These guidelines focus primarily on aspects that should be considered in the
design of the hold-time studies during the manufacture of non-sterile solid dosage
forms. Many of the principles described here also apply to other dosage forms
such as liquids, creams and ointments. These guidelines do not cover aspects for
hold times in cleaning validation, or the manufacturing of active pharmaceutical
ingredients (APIs) or biologicals.
These guidelines are intended as a basic guide for use by manufacturers
of pharmaceuticals and by GMP inspectors. This document is not intended to
prescribe a process for establishing hold times, but reflects aspects that should be
considered in the design of the hold-time study.
Manufacturers should gather scientific and justifiable data to demonstrate
that the dispensed raw materials and packaging materials, intermediate and
bulk products:
– remain of appropriate quality before processing to the next stage;
– meet the acceptance criteria.
The finished product should meet the release specifications.

Aspects to be considered
Hold time can be considered as the established time period for which materials
(dispensed raw materials, intermediates and bulk dosage form awaiting final
packaging) may be held under specified conditions and will remain within the
defined specifications.
Hold-time studies establish the time limits for holding the materials at
different stages of production to ensure that the quality of the product does not
produce results outside the acceptance criteria during the hold time. The design
of the study should reflect the holding time at each stage.
Hold times should normally be determined prior to marketing of
a product. The risk assessment of changes in processes, equipment, storage
conditions, starting or packaging materials should include an assessment of
whether further hold-time studies should be performed. Hold-time studies may
be included during development on pilot-scale batches or during scale-up, and
should be confirmed during process validation of commercial-scale processing
(1). Further data can also be collected as part of an investigation of a deviation
that occurred during manufacture.
Manufacturers may use a flow chart to review the manufacturing
procedure for a product and then break up the critical stages of the manufacturing
process on the basis of the time period required for the particular storage
and processing stages, typical pauses in the manufacturing campaign, and
the potential impact of storage with reference to environmental and storage
conditions. An example of a flow chart is given in Figure A4.1.
As an example, for oral tablets that are coated, the following stages may
be considered:
– binder preparation to granulation – consider the granulate;
– wet granulation to drying – consider the dried granulate;
– dried granules to lubrication/blending – consider the lubricated blend;
– blend to compression;
– compression to coating – consider the tablet cores;

– coating solution to preparation – consider the coating solution;
– coating to packing – consider the bulk coated tablets;
– coating to packing in bulk;
– packing of bulk to finished packed dosage form.

Figure A4.1
Example of a flow chart for reviewing the manufacturing procedure

A written protocol, procedure or programme should be followed,
which includes, for example, the activities to be performed, test parameters
and acceptance criteria appropriate to the material or product under test. The
protocol and report should generally include the following: a title; reference
number; version; date; objective; scope; responsibility; procedure; description
of the material or product; sample quantities; sampling method and criteria;
acceptance limits; frequency of sampling; sampling locations; pooling of samples;
storage conditions; type of container; methods of analysis; results; conclusion;
recommendation; signatures; and dates. Acceptance criteria are typically more
stringent than registered specifications, to provide assurance that the material is
well within control. When setting the specifications, any known stability trends
will need to be taken into account.
For certain products, microbiological aspects should also be considered
and included where appropriate.
All testing of bulk intermediates and product should be performed using
validated stability-indicating methods.
Typically one or more batches of a material, intermediate or product
can be used for determining hold times. A risk-based approach can be used to
determine the appropriate number of batches, considering the characteristics of
the materials and other relevant aspects. A representative sample of the batch
of material or product subjected to the hold-time study should be held for the
defined hold period. The hold period for each category of material should be
established on the basis of the study by keeping the material in either the original
or simulated container used in production. The containers in which hold-time
samples are stored should be the same pack as is used in production unless the
pack is exceptionally large, in which case one that is equivalent (constructed of
the same material and using the same closure system as the production packaging
system) may be used. Reducing the size of container, when this is necessary for
testing holding time, should be justified.
Where the headspace of containers used for bulk storage in manufacturing
and/or quarantine is important, for example, because of a risk of potential
degradation as a result of oxidation, then the hold-time studies should represent
worst-case conditions. In such cases, the ratio of headspace to contents in the
test containers should be at least as great as the maximum that is possible in
routine production (especially taking into account part-filled containers). The
environmental conditions for sample storage should be the same as those of the
quarantine area/manufacture stage. A sampling plan should be established and
followed for taking samples for testing at the different intervals. The amount of
sample required should be calculated based on the batch size, the intervals, and
the tests to be performed. Results should be compared with the initial baseline
data on the control sample. Samples may be pooled for analysis where appropriate,

e.g. when the analysis of a composite sample will not lead to issues that would be
detectable in single samples being missed when the samples are pooled.
Where appropriate, statistical analysis of the data generated should be
performed to identify trends and to justify the limits and hold time set.
Batches of finished products made from intermediates or bulk products
and subjected to a hold-time study should be considered for long-term stability
testing if data show adverse trending or shifting patterns during the intermediate
time points up to the end of the shelf-life. The shelf-life of the product – irrespective
of hold times – should be measured from the time the active ingredients are
mixed with other ingredients. Normally, intermediate and bulk products should
not be stored beyond the established hold time.

Table A4.1 provides examples of stages, study times and tests that may be
considered for a coated tablet.

Reference

1. Supplementary guidelines on GMP: validation, non-sterile process validation. In: WHO Expert
   Committee on Specifications for Pharmaceutical Preparations: forty-ninth report. Geneva: World
   Health Organization; 2015: Annex 3 (WHO Technical Report Series, No. 992).